ABSTRACT Although severity of post-mortem neuropathology is usually a good predictor of ante-mortem cognitive function, up to 30 percent of cognitively healthy subjects are found to harbor substantial pathology at autopsy. Both lifestyle and genetic factors likely contribute to their cognitive resilience, but until recently, only epidemiological features such as education or diet could be linked to diminished risk for dementia. The limitation on genetic analyses has now been overcome with the advent of well characterized prospective cohorts such as the Religious Orders Study and Memory and Aging Project in which genotype-phenotype associations can be tested. Our colleagues used SNP genotyping for over 1000 subjects from the ROSMAP study to test for association with residual cognitive function prior to death after factoring in age, education, gender, and 10 neuropathological measures. Eight loci were associated with cognitive resilience, 5 of which were confirmed by association between residual cognitive score and local methylation profile. Of the 5 gene candidates, DLGAP2 was particularly intriguing for its known role as a scaffolding protein in the post-synaptic density. Importantly, mRNA expression of DLGAP2 was positively correlated with residual cognitive function, suggesting it may provide structural protection from synaptic degeneration in response to Abeta accumulation or subsequent insult. Here we will test the hypothesis that DLGAP2 is a positive modifier of synaptic strength and cognitive function that contributes to brain reserve in protected individuals. Studies will focus on mouse models where we will test cognitive function, synaptic strength, and neuronal structure in response to gain or loss of DLGAP2 protein. We will further assess how DLGAP2 levels interact with both positive and negative risk factors for dementia including cognitive stimulation, amyloid pathology, and aging. Our studies will define how DLGAP2 promotes resilience under the opposing conditions that influence cognitive health. Our work offers a systematic approach for defining gene function in the healthy brain and identifying the conditions under which gain or loss of the candidate protein prolongs cognitive strength. Our studies will provide a pioneering entree into the previously impenetrable interactions between genetics, environment, aging, and disease that shape our cognitive healthspan.